Pharmacologically active tricyclic quinazolinones

ABSTRACT

The compounds are biologically active tricyclic quinazolinones of the class of imidazo(2,1-b)quinazolin-5-ones, pyrimido(2,1b)quinazolin-6-ones and diazepino(2,1-b)quinazolin-7-ones, useful, for example, as bronchodilator agents. Processes for preparation of said compounds include the reaction of a N-carboxy anthranilic anhydride (an isatoic anhydride) with a cyclic pseudothiourea such as 2-organomercapto-4,5-dihydroimidazole or 2-organomercapto-3,4,5,6-tetrahydropyrimidine.

United States Patent [191 Hardtmann 1 June 3, 1975 PHARMACOLOGICALLYACTIVE TRICYCLIC QUINAZOLINONES [75] Inventor: Guetz E. I-Iardtmann,Florham Park,

[73] Assignee: Sandoz, Inc., East Hanover, NJ.

[22 Filed: Jan. 19, 1973 211 App]. No.: 324,996

Related US. Application Data [63] Continuation-in-part of Ser. No.163,105, July 15, 1971, abandoned, which is a continuation-in-part ofSer. No. 87,016, Nov. 4, 1970, abandoned, which is acontinuation-in-part of Ser. No. 828,757, May 28, 1969, Pat. No.3,598,823.

[52] US. Cl 260/2564 F;

260/244 A; 260/2564 Q; 260/251 QA;

[51] Int. Cl C07d 51/42 [58] Field of Search 260/2564 F [56] ReferencesCited UNITED STATES PATENTS 3,257,401 6/1966 Wagner 260/2564 F 3,598,8238/1971 Hardtmann 260/2564 F 3,621,025 11/1971 Jen 260/2564 F 3,790,5732/1974 Blackburn ct a1. 260/2564 F OTHER PUBLICATIONS Jen, et a1, Journ.of Med. Chem," Vol. 15, No. 7, 1972 pp. 727-731.

Primary ExaminerDonald G. Daus Assistant Examiner-James l-l. TurnipseedAttorney, Agent, or FirnzGerald D. Sharkin; Richard E. Vila [5 7ABSTRACT 52 Claims, N0 Drawings PHARMACOLOGICALLY ACTIVE TRICYCLICQUINAZOLINONES This application is a continuation-impart of my nowabandoned copending application Ser. No. 163,105, filed July 15, l971which in turn is a continuation-inpart of abandoned application Ser. No.87.016, filed Nov. 4, 1970 which in turn is a continuation-in-part ofapplication Ser. No. 828,757, filed May 28, 1969, now US. Pat. No.3,598,823.

The present invention relates to tricyclic compounds which arequinazolinones, and to their preparation. The invention also relates topharmaceutical methods and compositions for utilization of the compoundsbased on their biological activity.

The compound 2,3-dihydro-lO-ethyl-imidazo[2,l b]quinazolin-( lOH)-one,and a method for preparing it, are known from Doleschall, et al., ActaChim. Hung. 45, 357360[ 1965]. The article contains no indicationwhatsoever, however, that the compound possesses pharmacologicalactivity. The only reference to pharmacological activity in the articleis to the effect that certain other related compounds were tested foractivity against various viruses but were found to be inactive. l havefound, however, as will be discussed in more detail hereinafter, thatthe compounds of the formula l hereinafter are pharmacologically active,in particular that they have, inter alia, bronchodilator activity.

The present invention is one aspect thereof provides for the effectingof pharmacological activity in animals by the administration of acompound of the formula I:

each of R and R is, independently, hydrogen, halo of atomic weight notgreater than 36 or lower alkyl of l to 3 carbon atoms, or are eitherboth hydroxy or both lower alkoxy of 1 to 2 carbon atoms; or one ishydrogen and the other bromo, hydroxy or lower alkoxy of l to 2 carbonatoms,

n is l to 3; and

R is lower alkyl of l to 5 carbon atoms,

Y H Y Y CH r or -(CH2)m-CH X X is a direct bond or (CH y is l to 3; m isO to 2,

each of Y and Y is, independently, hydrogen, halo of atomic weight notgreater than 36. i.e., fluoro or chloro, or lower alkyl of l to 3 carbonatoms, or either both are hydroxy or both are lower alkoxy of 1 to 2carbon atoms, or one is hydrogen and the other bromo, hydroxy or loweralkoxy of l to 2 carbon atoms, provided that no more than two of Rwherein R R and R are as defined, with a compound of formula III:

RS N

wherein n is as defined and R is lower alkyl or benzyl.

The preparation of compounds I by the reaction of Step A can be carriedout at temperatures in the range of 20C. to 160C, more usually 20C. to140C, preferably C. to C. The reaction is conveniently carried out in anorganic solvent of conventional type providing an inert reaction medium.The aromatic solvents and cyclic ethers suitable for use at refluxtemperatures represent the preferred solvents, e. g., toluene anddioxane. The reaction is preferably carried out in the presence of abase, e.g., sodium hydroxide or sodium carbonate; and when the compoundIII is employed directly in acid addition salt form, it is of coursedesirable to employ an amount of base somewhat greater than the amountnecessary to neutralize the acid. In general, the reaction product offormula I may be recovered from the reaction of Step A by working up byconventional procedures.

The compounds of formula I other than those bearing a hydroxysubstituent may also be prepared be reacting in a Step B a compound ofthe formula IV:

with a cyclizing agent, and treating the reaction product with anacid-binding agent.

The preparation of compounds I from compounds IV involves a cyclizationof known type carried out by treating a compound IV with a reagentsuitable for such type of cyclization, for example, a phosphorus halideor thionyl halide in which the halide has an atomic weight of from 35 to80, i.e., the chloride or bromide, more III preferably the chloride. Thepreferred reagent is thionyl chloride. The reaction with the cyclizingreagent may be carried out in absence of a solvent or in the presence ofinert solvents of known type. efg. the halogen-containing hydrocarbonssuch as methylene chloride and chloroform, and the aromatic solventssuch as benzene and pyridine. An excess of the cyclizing agent may,however, where appropriate. be employed to provide a solvent. Thetreatment with an acid-binding agent, e.g., an inorganic base ortertiary amine, is preferably effected after removal of the remainingcyclizing reagent. The reaction product of formula I may be isolatedfrom the reaction mixture by working up by established procedures.

The compounds of the formula I bearing a hydroxy substituent, i.e. oneor more of R R Y and Y is hydroxy. are most preferably prepared in aStep C reaction by hydrolysis of the corresponding alkoxy substitutedcompound of the formula I. The hydrolysis of Step C may be carried outin a conventional manner employing the usual conditions generallyutilized for converting an alkoxy group to a hydroxy group. e.g., bytreatment of said alkoxy compound of the formula I with aqueoushydrobromic acid at elevated temperature, e.g., 40C. to l50C.

The compounds of the formula II and Ill employed as starting materialsin the reaction of Step A are either known or may be prepared from knownmaterials by established procedures.

The compounds of formula IV may be prepared by reacting a compound ofthe formula V:

R it an 1 T v 2 N wherein R, R, R and R are as defined, with a compoundof formula VI:

H NCH --(CH ),,OH

wherein n is as defined.

The preparation of the compounds IV from com pounds V and VI is suitablycarried out at temperature in the range of from 0C. to 120C, preferablyC. to 80C. An excess of compound VI is preferably employed. The reactionmay be carried out in the absence ofa solvent but is preferablyconducted in the presence of an inert organic solvent which may be anyof several of the well known types, preferably a chlorinecontaininghydrocarbon such as chloroform and methylene chloride. The reactionproduct of formula IV may be isolated from the reaction mixture for usein preparation of compounds I by working up by established procedures.

The compounds of formula V may be prepared by reacting a compound offormula VII:

VII

wherein R, R and R are as defined. with an iodo compound of formulaVIII:

VIII

wherein R is as defined.

The preparation of compounds V by reacting of compounds VII and VIII issuitably carried out at tempera tures in the range of from 0C. to C,preferably 15C. to 60C. The reaction is desirably effected in thepresence of an inert organic solvent which may be any of several wellknown types, preferably a lower alcohol of l to 5 carbon atoms or anether, e.g.. ethanol and dioxane, preferably ethanol. The reactionproduct of formula V may be isolated from the reaction mixture for usein preparation of compounds IV by working up by established procedures.

The compounds of the formulae VII and VIII are either known or may beprepared from known materials by established procedures.

Also within the scope of the compounds of formula I of the invention arepharmaceutically acceptable salts not materially depreciating thepharmacological effect of the compounds. Such salts include the acidaddition salts of known type, e.g., the hydrochloride. The acid additionsalts may be produced from the corresponding free bases by conventionalprocedures. Conversely, the free bases may be obtained from the salts byprocedures known in the art.

The compounds of formula I of the invention are useful because theypossess biological activity. In general, the compounds possess inanimals one or more pharmacological activities such as bronchodilatoractivity, hypotensive activity, and central nervous system activity. Inparticular, the compounds of the formula I in which R is alkyl or aphenyl or substituted phenyl ring separated from the ring nitrogen by analkylene moiety, i.e., the compounds of the following formulae Ia. lband lo:

R N N l R T- (3H Ia N N 1 3 N--( and cH -lca N 1 \F N \1 R R2 2 n whichR,. R Y. Y and n are as defined and p is l or 2 and R is alkyl of l to 5carbon atoms are useful as bronchodilator agents as indicated bymeasuring bronchial resistance on intravenous administration (0.1 5mgs./kgs.) in the anesthetized guinea pig and according to the test ofKonzett and Rossler, Arch. Exp. Path. and Pharmak. 195271 (1940 and byobserving the respiratory status on oral administration (0.5 100mgs./kgs.) to the unanesthetized guinea pig exposed to aerosolizedhistamine dihydrochloride according to a modification of the method ofVan Arman. et al., J. Pharm. pharmacol. Exptl. Therap. 133190-97, 1961;and in vitro by observing the effect (0.1 micrograms/ml.) on strips ofguinea pig trachea according to the method of Constantine, J. Pharm.PharmacoL 17: 384- 385, 1960. For such use and depending upon knownvariables satisfactory results are obtained in general on the dailyadministration of from 0.3 to 100 milligrams per kilogram of bodyweight. preferably given in divided doses 2 to 4 times a day, or insustained release form. For most mammals the administration of from 20to 1,500 milligrams per day provides satisfactory results and dosageforms suitable for internal administration comprise 5 to 950 milligramsof the compound in admixture with a solid or liquid pharmaceuticalcarrier or diluent.

The compounds of the formula 1 in which R is phenyl or substitutedphenyl or cycloalkyl or cycloalkylalkyl,

i.e. the compound of the following formulae 1d and le: 7

1 N W Id and n a x f J N N Ie 1 W l R2 N 2 n wherein R R Y. Y. X, m andn are as defined. are also useful as hypotensive/antihypertensive agentsas indicated by a lowering of blood pressure on intrave nousadministration to the anesthetized dog For such use and depending uponknown variables satisfactory results are obtained in general on dailyadministration of from 0.1 to 100 milligrams per kilogram of bodyweight. For most mammals the administration of from 40 to 1,500milligrams per day provides satisfactory re sults and dosage forms forinternal administration comprise from 10 to 750 milligrams incombination with a suitable carrier. The preferred compounds foreffecting a lowering of blood pressure are those in which R iscycloalkylalkyl, n is l or 2 and R and R are hydrogen, more preferably Ris cyclopropylmethyl and/or n is l.

The preferred compounds of the invention from the standpoint ofbronchodilator activity, e.g., in the histamine aerosol assay, are thosein which R is benzyl including substituted benzyl. particularlyunsubstituted benzyl and more particularly those which have one or twofluoro substituents on the benzyl moiety. especially one, or have a 4-halo substituted-benzyl. and the more preferred such compounds arethose in which each of R, and R is hydrogen, and those in which n is lor 2, e.g., l0-benzyl-2,3-dihydro-imidazo12,l-b]quinazolin- 5(10H)-one.The especially preferred such bronchodilators from the standpoint ofexhibiting exceptional activity are those in which R is 4-halobenzyl(i.e. 4- fluoro-. 4-chloroand 4-bromobenzyl), particularly those inwhich n is l, e.g, l0-(4-chlorobenzyl)-2,3 dihydro-imidazol3.l-b]quinazolin-5( l0l-l)-one and 1(1-4-fluorobenzyl)-2,3-dihydro-imidazo[ 2,1- b]quinazolin-5( 10H)-one.

The compounds of the invention in which at least one of R and R is haloand/0r R is phenyl including substituted phenyl also exhibit CentralNervous System activity. Thus, the compounds of the formula I in which nis l and at least one of R and R is halo and those in which n is l and Ris phenyl including substituted phenyl, as represented by the compoundsof Examples 2A and 13A hereinafter, are also indicated as useful ananti-depressants by effectinng a reversal of reserpine hypothermia inmice. For this use the compounds may be administered generally toanimals at a daily dose of from 1 to milligrams per kilogram of bodyweight with the daily dosage for most mammals being in the range of 75to 1,000 milligrams, and with divided doses containing about 18 to 500milligrams.

In addition, the compounds of the formula I in which R is alkyl, atleast one of R, and R is halo and n is 2 or 3, as represented by thecompounds of Examples 1 and 2 are also indicated as useful as analepticagents by having a CNS stimulant effect in behavior tests in mice and byeffecting an antagonism of hexobarbital anesthesia in mice. For this usesatisfactory results are obtained on the administration of from 0.5 to50 milligrams per kilogram of body weight (i.v.), and the dosage formost mammals is in the range of from 35 to 500 milligrams i.v.p.r.n.Also, the compound of Example 138 is indicated as useful as atranquilizer/sedative by exhibiting a mixed CNS response in behaviortests in mice and by exhibiting in animals an antagonism to amphetaminein mice and a reinduction of hexobarbital in mice. For such usagesatisfactory results may be obtained in general at daily dosages of from4 to I milligrams per kilogram of animal body weight with the daily dosefor most mammals being in the range of about 300 to 3,000 milligrams.

Apart from the analeptic use indicated above, the compounds may becombined with a pharmaceutically acceptable carrier, and such otherconventional adjuvants as may be necessary, and administered orally orparenterally. For most uses, oral administration with carriers ispreferred and may take place in such conventional forms as tablets,dispersible powders, granules, capsules, suspensions, syrups andelixirs. Such compositions may be prepared according to any method knownin the art for the manufacture of pharmaceutical compositions. and suchcompositions may contain one or more conventional adjuvants, such assweetening agents, flavoring agents, coloring agents and preservingagents, in order to provide an elegant and palatable preparation.Tablets may contain the active ingredient in admixture with conventionalpharmaceutical excipients, e.g., inert diluents such as calciumphosphate, calcium sulphate dihydrate, lactose and talc, granulating anddisintegrating agents, e.g., starch and alginic acid, binding agents,e.g., starch, gelatin,

polyvinyl pyrrolidone and acacia, and lubricating agents, e.g.,magnesium stearate, stearic acid and tale. The tablets may be uncoatedor coated by known techniques to delay disintegration and adsoprtion inthe gastrointestinal tract and thereby provide a sustained action over alonger period. Similarly, suspensions, syrups and elixirs may containthe active ingredient in ad mixture with any of the conventionalexcipients utilized for the preparation of such compositions, e.g.,suspending agents (methylcellulose, tragacanth and sodium alginate),wetting agents (licithin, polyoxyethylene stearate and polyoxyethylenesorbitan monooleate) and preservatives (ethyl-p-hydroxy'benzoate).Capsules may contain the active ingredient alone or admixed with aninert solid diluent, e.g., calcium carbonate, calcium phosphate andkaolin. The preferred pharmaceutical compositions from the standpoint ofpreparation and ease of oral administration are solid compositions.particularly hard-filled capsules and tablets. Parenteral administrationmay be in such conventional forms as injectionable solutions andsuspensions and may be preferred or required in certain situations aswill be evident, for example, when desiring to employ certain of theabove-indicated compounds as analeptic agents.

A representative formulation is a tablet for oral administration 2 to 4times a day for prophylatic treatment of bronchial asthma and preparedby conventional tabletting techniques to contain the followingingredients:

A representative formulation is also a capsule for oral administration 2to 4 times a day for prophylatic treatment of bronchial asthma andprepared by conventional capsulating techniques to contain the followingingredients:

Capsule Ingredients Weight (Mg) lO-(4-Iluoroben7yl)-2.3-dihydroimidazolZ,l-b]quinazolin-5( l(lH)-one I0 Lactose 31oSterotex K (a triglycerol ester lubricant) I imidazoIZ.l-b]quinazoIin-5(lOH)-one 0.4 2071 Ethyl alcohol IO 40% Ascorbic acid I l07r Freon ll IO307: Freon I l4 l0 307: Freon I2 30 6071 Buffer System pH control q.si

Flavor q.s.

A representative formulation is a tablet for oral administration 2 to 4times a day for effecting a reduction in blood pressure and prepared byconventional tabletting techniques to contain the following ingredients:

Ingredients Weight (mg) I O-cyclopropyl-Z,3-dihydro-imidazo[2.l-b]quinazolin-5( lOH)one 25 Tragacanth l0 Lactose 222.5 Corn Starch25 Talcum 15 Magnesium Stearate A representative formulation is also acapsule for oral administration 2 to 4 time a day for prophylatictreatment of bronchial asthma and prepared by conventional capsulatingtechniques to contain the following ingredients:

Capsule Ingredients Weight (mg) l0-cyclopropyl-2.B-dihydro-imidazo [2.1-blquinazolin-5( IOH )-one l0 Lactose 3l6 Sterotex K (a triglycerolester lubricant) 10 The following examples show representative compoundsencompassed within the scope of this invention and the manner in whichsuch compounds are prepared. However, it is to be understood that theexamples are for purposes of illustration only.

EXAMPLE I l 1-MethyI-8-chloro-2,3,4,ll-tetrahydropyrimido[2,lblquinazolin-6-one A mixture of l2.5 g. ofo-chloro-N-methylisatoic anhydride, 6.5 g. of 2 -methylmercapto-345,6-tetrahydropyrimidine and one pellet of sodium hydroxide is refluxed in200 ml. of dioxane for 18 hours. The cooled mixture is filtered throughCelite and most of the solvent is evaporated. The residue is taken up inmethylene chloride. the solution extracted with water, dried, treatedwith charcoal and evaporated to obtain an oily residue which iscrystallized from diethyl ether to obtain l l-methyl-8chloro-2,3,4, 1l-tetrahydropyrimido[2,l-b]quinazolin-6-one, m.p. l l9l20C. Additionalamounts of this product could be obtained by working up the motherliquor by chromatography on silica gel and thereafter crystallizing frommethylene chloride containing 5% methanol.

EXAMPLE 2 The following compounds of the invention are preparedemploying the reaction which is exemplified in Example 1.

A. 7-chloro-2,3-dihydro- 1 -methyl-imidazo[ 2, 1

b]quinazolin-( lOH)-one, m.p. 200202C.

B. 9-chloro-l2-methyl-2,3,4,5-tetrahydro(12H)- diazepino [2, l-b]quinazolin-7-one, m.p. 1 1 8-1 19C.

C. 2,3-dihydrol O-methyl-imidazo[ 2, 1-b]quinazolin- 5(lOl-l)-one, m.p.2l32l5C. D. 8-chloro2,3-dihydro-l0-methyl-imidazo[2,l-b]

quinazolin-5( lOH)-one, m.p. 277279C.

7,8-dimethoxy-2,3-dihydro-lO-methylimidazo[2, l -b] quinazolin-5(lOH)-one, 253256C.

2,3-dihydro- -ethyl-7-chloro-imidazo[ 2,1- b]quinazolin-5( l0H)-one,m.p. 154-156C. G. 7-chloro-2,3dihydrol O-benzyl-imidazo[2, l

b]quinazolin-5( lOH)-one, m.p. 189-l9lC.

7,8-dimethoxy-2,3-dihydro-l0-benzylimidaz0[2,l-b] quniazolin-5(l0H)-one, m.p. l87189C. I. l 1-benzyl-2,3,4-1 l-tetrahydropyrimido[2,1-

b]quinazolin-6-one, m.p. l58l60C.

J. 2,3-dihydro-10-ethyl-imidazo[2,l-b]quinazolin- 5(lOH)-one.

K. 8-chl0rol0-benzyl-2,3 ,-dihydro-imidazo[ 2, l b]quinazolin-5(l0H)-onemethanesulfonate, m.p. 251-253C.

L. l2-benzyl-2,3,4,5-tetrahydro-(12H)- diazepino[2,l-b]quinazolin-7-one, m.p. l03105C.

M. lO-isopropyl-2,3-dihydro-imidazo[2,l-

b]quinazolin-5( lOH)-one, m.p. 149-l5lC.

EXAMPLE 3 2,3-Dihydrol 0-benzyl-imidazo[2 l -b]quinazolin- 5 10H )-oneEXAMPLE 4 7-Chloro-2,3-dihydro-lO-methyl-imidazo[2,1- b]quinazolin-5(lOH)-one (alternative procedure) Step 21. 6-Chlorol-methyl-2-methylmercapto-4- quinazolinone A mixture of 35 g. of6-chloro-l-methyl-2-thioquinazoline-2,4-dione. 500 ml. ethanol and 50 g.of methyl iodide is stirred at room temperature for 48 hours. Theethanol is evaporated off in vacuo to obtain a crude oil of6-chloro-l-methyl-2-methylmercapto-4- quinazolinone.

Step b. 6-Chloro-1-methyl-2-(2-hydroxyethyl)- an'iino-4-quinazolinone 38g. of the crude product obtained in (a) above is added to a solution ofg. of ethanolamine in 200 ml. of chloroform. The resulting mixture isstirred for 3 hours at room temperature and then warmed to 60C. for 30minutes while maintaining the stirring. The chloroform is thenevaporated off in vacuo, the residue poured onto 500 g. of ice-water andthe resulting system extracted 4 times each time with 300 ml. ofmethylene chloride. The combined organic phase is washed 3 times withwater and 3 times with saturated sodium chloride solution, dried, andevaporated in vacuo. The residue is then treated 3 times with toluenewhich is evaporated off in vacuo after each treatment to obtain a cruderesidue of 6-chloro-lmethyl-2-(2- hydroxyethyl)amino-4-quinazolinone.

Step 0. 7-Chloro-2,3-dihydro-lO-methylimidazo[2,l-b]quinazolin-5(lOH)-one 11 g. of the crude product obtained in (b) above is dissolvedin 30 ml. of thionyl chloride and the resulting mixture heated at 80C.for 3 hours. The solvent is evaporated in vacuo and the residue isdissolved in methylene chloride, extracted with sodium bicarbonatesolution and then with water, the organic phase dried, evaporated invacuo and the residue crystallized from methylene chloride/diethyl etherto obtain 7-chloro- 2,3-dihydrol O-metl1yl-imidazo 2, l b]quinazolin- 5(lOH)-one, m.p. 200-202C.

EXAMPLE 5 2,3-Dihydro- 1 0-benzyl-imidazo[ 2, l -b]quinazolin- 5(lOH)-one (alternative procedure) Step a.l-Benzyl-2-thio-l,2,3,4-tetrahydroquinazolin-4-one A suspension of 75 g.of N-benzylanthranilic acid in 500 ml. of pyridine was added portionwiseover an hour to a boiling solution of 32 g. of ammonium thiocyanate and47 ml. of benzoyl chloride in ml. of anhydrous acetone. The mixture wascooled and concentrated. The residue was mixed with 250 ml. of methanoland the crystalline precipitate was filtered and washed with water toobtain the heading compound.

Step b. l-Benzyl-2-methylmercapto-l,4-dihydroquinazolin-4-one A mixtureof 5 g. of the product obtained in (a) above, 40 ml. of ethanol and 4ml. of methyl iodide was stirred at room temperature for 3 hours. 4 ml.of 6N potassium hydroxide was added and the mixture allowed to standovernight. The precipitate was then filtered off, and washed with water,ethanol and ether to obtain the heating compound.

Step 0. l-Benzyl-2-( 2-hydroxyethyl)amino-4- quinazolinone A mixture of2.8 g. of the crude product from (b) above, 15 ml. of ethanolamine and40 ml. of chloroform was stirred at room temperature for 2 hours. Themixture was then heated at 60C. for 1 hour. The solvent was thenevaporated off in vacuo. and the residue dissolved in ethylacetate/benzene (1:1) and extracted three times with water. The organicphase was dried and evaporated in vacuo to obtain a crude residue of theheading compound.

Step d. 2,3-Dihydrol O-benzyl-imidazo( 2, l

b)quinazolin-5( H)-0ne 0.5 g. of the crude product was obtained in (c)above was dissolved in 10 ml. of thionyl chloride, and the resultingmixture heated at 80C. for 2 hours. The thionyl chloride was evaporatedin vacuo, the residue treated with ice-6N sodium hydroxide solution andthe solid dissolved in methylene chloride followed by extraction withwater and with saturated sodium chloride solution. After drying andevaporation in vacuo, the residue was crystallized from ether to obtain,the heading compound, m.p. 203204C.

EXAMPLE 6 STEP A: Preparation of N-(p-fluorobenzyl)isatoic anhydride Toa solution of 16.3 g. of isatoic anhydride in 200 ml. ofdimethylacetamide at room temperature is added sodium hydride obtainedfrom 5.0 g. of 57% solution in mineral oil. The resulting mixture isstirred for minutes and 16 g. of p-fluorobenzyl chloride is addedfollowed by stirring at room temperature for about 15 hours. Theresulting mixture is concentrated in vacuo to about one half its volume,a mixture of ice and water added and the resulting precipitate filteredoff, washed with water, dried under suction and washed with pentane. Thesolid material is then dissolved in methylene chloride, dried withsodium sulfate, treated with charcoal and about twice the volume ofdiethyl ether added to crystallized N-(p-fluorobenzyl)isatoic anhydride,m.p. l42l45C.

STEP B: Preparation of l0-(4'-fluorobenzyl)-2,3-

dihydro-imidazo [2,l-b]quinazoline-5( l0H)-one A solution of 5.4 g. ofN-(p-fluorobenzyl)isatoic anhydride, 2.5 g. ofZ-methylmercapto-imidazoline and one pellet (about 100 mg.) sodiumhydroxide in 75 ml. of dioxane is refluxed with stirring for 4 hours.The resulting mixture is evaporated to dryness, the residue dissolved inmethylene chloride, washed with water and extracted twice with 1Nhydrochloric acid. The combined aqueous extracts are washed withmethylene chloride and then with diethyl ether and made basic withsodium bicarbonate. The resulting precipitate is 12 filtered off, washedthoroughly with water, dried by suction, dissolved in methylenechloride, dried with sodium sulfate, treated with charcoal and themethylene chloride exchanged for methanol to crystallize lO-(4-fluorobenzyl)-2.3-dihydro-imidazo [2,l-b]quinazolin- 5(1OH)-one, m.p.l92-l95C.

EXAMPLE 6A A suspension of the final product of Example 3 in the amountof 3.6 g. in 30 ml. of absolute ethanol is saturated with anhydroushydrogen chloride under ice cooling to form a solution which isconcentrated in vacuo to one half its volume, charcoal added and thesolution filtered through celite. About 50 ml. of diethyl ether is thenadded to crystallize l0-(4'-fluorobenzyl)-2,3-dihydro-imidazo[2,l-b]quinazolin-5( lOH)-one hydrochloride, meltingat 235-238c. and again at about 320C.

EXAMPLE 7 The following additional compounds of the invention areprepared employing the reactions exemplified in Examples 6 and 6A:

A. ll-(3',4-dimethoxybenzyl)-2,3,4-1 ltetrahydropyrimido[2.l-b]quinazolin-6-one, m.p. l42-l44C.

lO-(4-methylbenzyl)-2,3-dihydro-imidazo[2,l-

b]quinazolin-5(l0H)-one methanesulfonate, m.p.

l0-(2'-methylbenzyl)-2.3-dihydro-imidazo[2,1-

b]quinazolin5( l0H)-one methanesulfonate, m.p.

D. lO-phenethyl-Z,3-dihydroimidazol2,1-

b]quinazolin-5(l0l-l)-one methanesulfonate, m.p.

lO-(3',4'-dimethoxybenzyl)-2,3-dihydroimidazo[2,l-b]quinazolin-5(lOH)-one methanesulfonate, m.p. 180-182C.

10-(amethyl-benzyl)-2,3-dihydro-imidazo[2,1 b]quinazolin-5( 10H)-one,m.p. l36l38C.

G. l0-benzyl-7-methoxy-2,3-dihydro-imidazo[2,1-

b]quinazolin-5(1OH)-one, m.p. l73l75C.

H. l0-(3,4-dimethoxybenzyl)-2,3,4,5-tetrahydro-(l2H)-diazepino[2,l-b]quinazolin-7-one, m.p. l34-l36C.

l. ll-(4-fluorobenZyl)-2,3,4,l l-

tetrahydropyrimidol2,l-b] quinazolin-6-one, m.p. l54-156C.

J. 8-chloro-l0-(4-fluorobenzyl)-2,3-dihydroimidazo[2,l-b]quinaZolin-5(10H)-one, m.p.

l0-( 3 -fluorobenzyl )-2,3-dihydro-imidazo[2, l

b]quinazolin-5(1OH)-one hydrochloride, m.p.

b]quinazolin-5(lOH)-one hydrochloride, m.p.

M. l0-(4'-chlorobenzyl)-2,3-dihydro-imidazo[2,1-

b]quinazolin-5( 10H )-one.

N. lO-(3',4-difiuorobenzyl)-2,3-dihydroimida2o[2,l-b]quinazolin-5(l0H)-one, m.p. 209-2llC.

O. l0-(4'-bromobenzyl)2,3'dihydro-imidazo[2,1-b]

quinazolin-5( l0H)-one, m.p. l-l77C.

lO-(2',6'-dichlorobenzyl)-2,3-dihydroimidazo[2,l-b]quinazolin-SUOl-U-one, m.p.

EXAMPLE 8 l-Benzyl-7-hydroxy-2,3-dihydro-imidazo[2,lb]quinazolin-(l0H)-one O HO One gram of l0-benzyl-7-methoxy-2,3-dihydro imidazo[2,l-b]quinazolin-5(l0l-l)-one is added slowing to ml. of 48% hydrobromic acidand the resulting mixture refluxed with stirring for 2 hours. Theresulting mixture is cooled and the precipitated material filtered offand dissolved in IN. sodium hydroxide. The resulting solution is washedtwice with methylene chloride and slowly acidified to about pH6 with 2Nhydrochloric acid to form a crystalline material which is filtered off,washed with water, dried by suction and dissolved in chloroform and aminor amount of methanol, treated with charcoal and concentrated on astream bath to crystallized l0-benzyl-7-hydroxy-2,3-dihydroimidazo[ 2, l-b] quinazolin-5( l0H)-one, m.p. 225-227C.

EXAMPLE 9 Step A. Preparation of N-(p-fluorobenzyl)isatoic anhydride Toa solution of 3.2 kgs. isatoic anhydride in kgs.

dimethylacetamide is added under nitrogen with stirring sodium hydrideobtained from 880 gms. of a 57% The reaction mixture is. then cooled to20 C. and to it is added 3.0 kgs. p-fluorobenzyl chloride. Themixture'is-then reheated to about 60C. and held there for about 4hours.It is then cooled again to 20C and to it is added 17.4 kgs. of ice andthen 24 kgs. water. The mixture is stirred for 15 minutes, the solidscollected by filtration, washed with several 2 kg. portions of water andthen three times with 0.7 kg. diethylether. The washed solids are driedto obtain N-(pfluorobenzyl)isatoic anhydride, m.p. l40l43C.

Step B: Preparation of l0-(4-fluorobenzyl)-2,3-

dihydroimidazo [2,l-b]quinazolin-5( l0H)-one A charge of 26 kgs.toluene, 2,5kgs. 2-methylmercaptoimidazoline hydroiodide, 2.4 kgs.N-(pfluorobenzyl)isatoic anhydride and 1.55 kgs. powdered anhydroussodium carbonate is refluxed for 18 20 hours in a reaction vessel whichis vented to a caustic gas washing tower. Any water formed during thereaction is collected in a Dean-Stark separator. The reaction is cooledto 20C. and 10 kgs. water added. The mixture is stirred for about 30minutes and the solids collected, washed several times with 2 kg.portions of water, and three times with 0.8 kg. toluene. The solids arethen dried at reduced pressure (about 55C.) to obtain a crude productm.p. l96l98C. The crude is dissolved at 50C. in a solution of 14 kgs.chloroform and v 4kgs. ethanol and treated in solution with 0.1 kg.decoldispersion in mineral oil, while maintaining the temperature below25C. The resulting mixture is heated to about 60C. and held at about 5560C. for one hour.

oring charcoal for about 10 minutes. The charcoal is removed byfiltration through a celite bed and solids reprecipitated byconcentrating the filtrate to a volume of about 8 liters. Thisconcentrate is cooled to 05C., the solids collected by filtration,washed with cold ethano] and then diethyl ether, and dried to reducedpressure to obtain l0-(4-fluorobenzyl)-2,3-dihydr0- imidazo[2,1-b]quinazolin-5( l0H)-one, m.p. l97198C.

EXAMPLE 10 l0-cyclopropylmethyl-2,3-dihydro-imidazo 2, l b]quinazolin-5(l0H)-one maleate STEP A: Preparation of N-(cyclopropyl)isatoic anhydrideTo a solution of 20 g. isatoic anhydride in 200 ml. dimethylacetamide isadded under nitrogen with stirring sodium hydride obtained from 6 g. ofa 57% dispersion in mineral oil, while maintaining the temperature below25C. The resulting mixture is stirred at 25C. for one hour and to it isadded 17 g. cyclopropylmethylbromide. The mixture is then stirred atroom temperature for about 20 hours. It is then poured on water. Themixture is stirred for 15 minutes, the solids collected by filtration,washed with several portions of water and then three times with 0.7 kg.of diethylether. The washed solids are dried to obtainN-(cyclopropylmethyl)isatoic anhydride, m.p. ll8l2lC.

STEP B: Preparation of lO-cyclopropylmethyl-2,3-

dihydroimidazo [2,1-b]quinazolin-5( lH)-one A charge of 100 ml. ofdioxane, 3.5g. 2-methylmercaptoimidazoline hydroiodide, 6 g.N-(cyclopropylmethyl)isatoic anhydride and 2 pellets of sodium hydroxideis refluxed for one hour in a reaction vessel. The reaction is cooled to20C. and the solvent evaporated. The residue is dissolved in methylenechloride and this solution is extracted with 1 normal hydrochloridesolution. The acid solution is extracted with methylene chloride(discard) and with ether (discard) and them made basic with 10% sodiumbicarbonate solution. The

precipitate which forms is filtered off, washed with water and dissolvedin methylene chloride. After drying with, anhydrous sodium sulfate, thesolvent is exchanged from ether and the product crystallized by additionof pentane. This material is con- 'verted into its hydrogen maleateaddition salt by conventional procedures to obtain 10-cyclopropylmethyl-2 ,3-dihydroimidazo[ 2, 1 b]quinazolin-5( lOH)-onehydrogen maleate, m.p. l89 192C.

EXAMPLE ll EXAMPLE 12 -p-Fluoro-phenyl-Z,3-dihydro-imidazo[2, lb]quinazolin-5( 10H)-one N N 2 N l 8 STEP A: Preparation ofN-(p-Fluoro-phenyl)isatoic anhydride The potassium salt ofo-chlorobenzoic acid g) 25 g. of 4-fluoroaniline, 9 g. potassiumcarbonate and 2 g..

of copper powder were heated under reflux in 200 ml. dimethylformamide.After cooling the solvent was evaporated, the residue dissolved in 500ml. of absolute ethanol, the solution was filtered and the filtrateevaporated. The residue was suspended in 300 ml. of methylene chlorideand filtered. The solid (on ten filter) was dissolved in 100 ml. ofwater and 45g. of potassium carbonate was added. To this solution ml.phosgene 12.5% in benzene) was added under vigorous stirring. Thestirring was continued for 18 hours at room temperature. Theprecipitate, which had formed, was filtered off and washed with water.After air drying the filter case was dissolved in chloroform (200 ml.)and the solution treated with solid sodium carbonate. aluminium oxideand activated charcoal. The solvent was then exchanged for ether and thematerial, which crystallized, was collected by filtration, m.p. 199-201.

STEP B: Preparation of lO-(p-fluoro-phenyl)-2,3-

dihydro-imidazo [2,l-b]quinazolin-5( 10H)-one A solution of 5.4 g. ofN-(p-fluoro-phenyl)isatoic anhydride, 2.5 g. ofZ-methylmercapto-imidazoline and one pellet (about 100 mg.) sodiumhydroxide in ml. of dioxane is refluxed with stirring for 4 hours. Theresulting mixture is evaporated to dryness, the residue dissolved inmethylene chloride, washed with water and extracted twice with 1Nhydrochloric acid. The combined aqueous extracts are washed withmethylene chloride and then with diethyl ether and made basic withsodium bicarbaonate. The resulting precipitate is filtered off, washedthoroughly with water, dried by suction, dissolved in methylenechloride, dried with sodium sulfate, treated with charcoal and themethylene chloride exchanged for methanol to crystallize10-(pfluoro-phenyl )-2,3 dihydro-imidazo 2, l -b]quinazolin-5(101-1)-one, m.p. 278280C.

EXAMPLE 13 The following compounds of the invention are preparedemploying the reaction which is exemplified in Example 12.

A. 2,3-dihydro-10-phenyl-imidazo[2,1-b]quinazolin- 5(10H)-one, m.p.297299C.

' 12-phenyl-2,3,4,5-tetrahydro-( 121-1)- -b] quinazolin-7-one, m.p.

diazepino[ 2,1 l8l9-183C. What is claimed is: l. A compound of theformula:

N N R Y W R 2 N '(CH )n X is a direct bond or (Cl-l Y is 1 to 3;

m is O to 2. each of Y and Y is. independently, hydrogen. fluoro, chloroor alkyl or 1 to 3 carbon atoms. or either both are hydroxy or bothalkoxy of l or 2 carbon atoms; or one is hydrogen and the other bromo.hydroxy or alkoxy of l to 2 carbon atoms. provided that no more than twoof R R Y and Y are hydroxy. further provided that neither of R, and R isl.ydroxy with either of Y and Y is alkoxy and further provided thatneither of Y and Y is hydroxy when either of R, and R is alkoxy, andstill further provided that one or both of R, and R. is fluoro or chloroor one is bromo or both are alkoxy or both hydroxy when R is alkyl and nis l. or a pharmaceutically acceptable acid addition salt thereof.

2. A compound of claim 1 in which-n is l and R is other than alkyl.

3. A compound of claim 1 in which R is and m is l or 2.

4. A compound of claim 3 in which each of R, and R is hydrogen.

5. A compound of claim 4 in which n and m are each l.

6. The compound of claim 5 which is l(l-benzyl-2,3-dihydro-imidazolZ.l-b]quinazolin-5( 10H )-onc.

7. The compound of claim 6 which is the free base form.

8. The compound of claim 5 which is l-(4'- fluorobenzyl)-2,3-dihydro-imidazo[ 2, l -b]quinazolinl0H)-one.

9. The compound of claim 8 in free base form.

10. The compound of claim 8 which is the hydrochloric acid additionsalt.

11. A compound of claim 3 in which each of R, and R is hydrogen, n is lor 2, m is 1, Y is fluoro. chloro or bromo at the 4-position and Y ishydrogen.

12. A compound of claim 11 in which n is l.

13. The compound of claim 1.2 which is -(4- chlorobenzyl2,3-dihydro-imidazol 2, l -b]quinazolin 5( lOH)-one.

14. The compound of claim 12 which is l0-(4- bromobenzyl)-2,3-dihydro-imidazol 2, l -b ]quina2olin- 5( lOH)-one.

15. The compound of claim 4 which ll-benzyl- 21. The compound of claim20 which is l(l-(amethylbenzyl )-.'l.3-dihydro-imidazol 2, l -blquinazolin- 5( 10H )-onev 22. A compound of claim 1 in which R is alkyland at least one of R, and R is selected from the group con sisting offluoro, chloro or bromo.

23. A compound of claim 1 in which R is alkyl and n is 2 or 3.

24. A compound of claim 23 in which R, is hydrogen and R is chloro.

25. A compound of claim 22 in which n is l.

26. A compound of claim 25 in which R, is hydrogen and R is chloro.

27. A compound of claim 1 in which each of R, and R is alkoxy.

28. A compound of claim 27 in which R is alkyl.

29. A compound of claim 4 in which in is 1, Y is hydrogen and Y isfluoro.

30. A compound of claim 3 in which n is l.

31. A compound of claim 3 in which R, and R is either hydrogen or alkyland Y is hydrogen or fluoro and Y is hydrogen or fluoro, chloro or bromoat the 4- position.

32. A compound of claim 3 in which n is 2.

33. A compound of claim 32 in which m is 1, each of R, and R ishydrogen, Y is hydrogen and Y is hydrogen or fluoro, chloro or bromo atthe 4-position.

34. A compound of claim 33 in which Y is fluoro. chloro or bromo.

35. The compound of claim 34 in which 1 l-(4- fluorobenzyl)-2,3,4.ll-tetrahydropyrimido[2.lblquinazolin-o-one.

36. A compound of claim 1 in which R is 37. A compound of claim 36 inwhich n is l.

38. A compound of claim 36 in which m is l or 2.

39. A compound of claim 38 in which n is l and m is l.

40. A compound of claim 39 in which each of R, and R is hydrogen.

41. The compound of claim 40 which iscyclopropylmethyl-Z,3-dihydro-imidazol2, l b]quinazolin-5( l()l-l)-one.

42. A compound of claim 36 in which n is 2.

43. A compound of claim 42 in which m is l to 2.

44. A compound of claim 36 in which in is 0.

45. A compound of claim 44 in which n is l.

46. A compound of claim 1 in which R is 47. A compound of claim 46 inwhich each of R, and R is hydrogen.

48. A compound of claim 46 in which n is l.

49. A compound of claim 46 in which n is 3.

50. A compound of claim 48 in which each of R, and R is hydrogen.

51. A compound of claim 4 in which in is l.

52. A compound of claim 51 in which Y is fluoro and Y is hydrogen.

1. A compound of the formula:
 1. A COMPOUND OF THE FORMULA:
 2. Acompound of claim 1 in which n is 1 and R is other than alkyl.
 3. Acompound of claim 1 in which R is
 4. A compound of claim 3 in which eachof R1 and R2 is hydrogen.
 5. A compound of claim 4 in which n and m areeach
 1. 6. The compound of claim 5 which is10-benzyl-2,3-dihydro-imidazo(2,1-b)quinazolin-5(10H)-one.
 7. Thecompound of claim 6 which is the free base form.
 8. The compound ofclaim 5 which is10-(4''-fluorobenzyl)-2,3-dihydro-imidazo(2,1-b)quinazolin-5(10H)-one.9. The compound of claim 8 in free base form.
 10. The compound of claim8 which is the hydrochloric acid addition salt.
 11. A compound of claim3 in which each of R1 and R2 is hydrogen, n is 1 or 2, m is 1, Y isfluoro, chloro or bromo at the 4-position and Y'' is hydrogen.
 12. Acompound of claim 11 in which n is
 1. 13. The compound of claim 12 whichis 10-(4''-chlorobenzyl-2,3-dihydro-imidazo(2,1-b)quinazolin-5(10H)-one.14. The compound of claim 12 which is10-(4''-bromobenzyl)-2,3-dihydro-imidazo(2,1-b)quinazolin-5(10H)-one.15. The compound of claim 4 which11-benzyl-2,3,4,11-tetrahydropyrimido(2,1-b)quinazolin-6-one.
 16. Thecompound of claim 5 which is10-(3''-fluorobenzyl)-2,3-dihydro-imidazo(2,1-b)quinazolin-5(10H)-one.17. The compound of claim 5 which is10-(2''-fluorobenzyl)-2,3-dihydro-imidazo(2,1-b)quinazolin-5(10H)-one.18. The compound of claim 5 which is10-(3'',4''-difluorobenzyl)-2,3-dihydro-imidazo(2,1-b)quinazolin-5(10H)-one.19. The compound of claim 5 which is10-(2''-methylbenzyl)-2,3-dihydro-imidazo(2,1-b)quinazolin-5(10H)-one.20. A compound of claim 1 in which R is
 21. The compound of claim 20which is 10-( Alpha-methylbenzyl)-2,3-dihydro-imidazo(2,1-b)quinazolin-5(10H)-one.
 22. Acompound of claim 1 in which R is alkyl and at least one of R1 and R2 isselected from the group consisting of fluoro, chloro or bromo.
 23. Acompound of claim 1 in which R is alkyl and n is 2 or
 3. 24. A compoundof claim 23 in which R1 is hydrogen and R2 is chloro.
 25. A compound ofclaim 22 in which n is
 1. 26. A compound of claim 25 in which R1 ishydrogen and R2 is chloro.
 27. A compound of claim 1 in which each of R1and R2 is alkoxy.
 28. A compound of claim 27 in which R is alkyl.
 29. Acompound of claim 4 in which m is 1, Y'' is hydrogen and Y is fluoro.30. A compound of claim 3 in which n is
 1. 31. A compound of claim 3 inwhich R1 and R2 is either hydrogen or alkyl and Y is hydrogen or fluoroand Y'' is hydrogen or fluoro, chloro or bromo at the 4-position.
 32. Acompound of claim 3 in which n is
 2. 33. A compound of claim 32 in whichm is 1, each of R1 and R2 is hydrogen, Y'' is hydrogen and Y is hydrogenor fluoro, chloro or bromo at the 4-position.
 34. A compound of claim 33in which Y is fluoro, chloro or bromo.
 35. The compound of claim 34 inwhich 11-(4''-fluorobenzyl)-2,3,4,11-tetrahydropyrimido(2,1-b)quinazolin-6-one.
 36. A compound of claim1 in which R is
 37. A compound of claim 36 in which n is
 1. 38. Acompound of claim 36 in which m is 1 or
 2. 39. A compound of claim 38 inwhich n is 1 and m is
 1. 40. A compound of claim 39 in which each of R1and R2 is hydrogen.
 41. The compound of claim 40 which is10-cyclopropylmethyl-2,3-dihydro-imidazo(2,1-b)quinazolin-5(10H)-one.42. A compound of claim 36 in which n is
 2. 43. A compound of claim 42in which m is 1 to
 2. 44. A compound of claim 36 in which m is
 0. 45. Acompound of claim 44 in which n is
 1. 46. A compound of claim 1 in whichR is
 47. A compound of claim 46 in which each of R1 and R2 is hydrogen.48. A compound of claim 46 in which n is
 1. 49. A compound of claim 46in which n is
 3. 50. A compound of claim 48 in which each of R1 and R2is hydrogen.
 51. A compound of claim 4 in which m is 1.